Neuroprotective effect of adult hematopoietic stem cells in a mouse model of motoneuron degeneration

Degenerative spinal motor diseases, like amyotrophic lateral sclerosis, are produced by progressive degeneration of motoneurons. Their clinical manifestations include a progressive muscular weakness and atrophy, which lead to paralysis and premature death. Current pharmacological therapies fail to stop the progression of motor deficits or to restore motor function. The purpose of our study was to explore the possible beneficial effect of mouse adult hematopoietic stem cells (hSCs) transplanted into the spinal cord of a mouse model of motoneuron degeneration. Our results show that grafted hSCs survive in the spinal cord. In addition, the number of motoneurons in the transplanted spinal cord is larger than in non-transplanted mdf mice at the same spinal cord segments and importantly, motor function significantly improves. These effects can be explained by the increased levels of glial cell line derived neurotrophic factor (GDNF) around host motoneurons produced by the grafted cells. Thus, these experiments demonstrate the neuroprotective effect of adult hSCs in the model employed and indicate that this cell type may contribute to ameliorating motor function in degenerative spinal motor diseases.     

Postnatal alterations of the inhibitory synaptic responses recorded from cortical pyramidal neurons in the Lis1/sLis1 mutant mouse

Mutations in the mouse Lis1 gene produce severe alterations in the developing cortex. We have examined some electrophysiological responses of cortical pyramidal neurons during the early postnatal development of Lis/sLis1 mutant mice. In P7 and P30 Lis1/sLis1 neurons we detected a lower frequency and slower decay phase of mIPSCs, and at P30 the mIPSCs amplitude and the action potential duration were reduced. Zolpidem (an agonist of GABAA receptors containing the alpha1 subunit) neither modified the amplitude nor the decay time of mIPSCs at P7 in Lis1/sLis1 neurons, whereas it increased the decay time at P30. The levels of GABAA receptor alpha1 subunit mRNA were reduced in the Lis1/sLis1 brain at P7 and P30, whereas reduced levels of the corresponding protein were only found at P7. These results demonstrate the presence of functional alterations in the postnatal Lis1/sLis1 cortex and point to abnormalities in GABAA receptor subunit switching processes during postnatal development.     

Proton dynamics in cancer

Cancer remains a leading cause of death in the world today. Despite decades of research to identify novel therapeutic approaches, durable regressions of metastatic disease are still scanty and survival benefits often negligible. While the current strategy is mostly converging on target-therapies aimed at selectively affecting altered molecular pathways in tumor cells, evidences are in parallel pointing to cell metabolism as a potential Achilles' heel of cancer, to be disrupted for achieving therapeutic benefit. Critical differences in the metabolism of tumor versus normal cells, which include abnormal glycolysis, high lactic acid production, protons accumulation and reversed intra-extracellular pH gradients, make tumor site a hostile microenvironment where only cancer cells can proliferate and survive. Inhibiting these pathways by blocking proton pumps and transporters may deprive cancer cells of a key mechanism of detoxification and thus represent a novel strategy for a pleiotropic and multifaceted suppression of cancer cell growth. Research groups scattered all over the world have recently started to investigate various aspects of proton dynamics in cancer cells with quite encouraging preliminary results. The intent of unifying investigators involved in this research line led to the formation of the "International Society for Proton Dynamics in Cancer" (ISPDC) in January 2010. This is the manifesto of the newly formed society where both basic and clinical investigators are called to foster translational research and stimulate interdisciplinary collaboration for the development of more specific and less toxic therapeutic strategies based on proton dynamics in tumor cell biology.     

8-hydroxy-2'-deoxyguanosine and lipid peroxidation in patients with heart failure

INTRODUCTION AND OBJECTIVES: Heart failure is associated with increased free radical production, which leads to a state of oxidative stress. Known markers of oxidative stress include 8-hydroxy-2'-deoxyguanosine, which reflects oxidative damage to DNA, and lipid peroxidation, which can be used to quantify damage to lipid-rich structures. The aims of this study were to compare 8-hydroxy-2'-deoxyguanosine and lipid peroxidation levels in heart failure patients and healthy subjects and to assess how these levels are influenced by heart failure etiology. METHODS: The study included 78 patients (57 male, age 64 [14] years) with heart failure and 12 control subjects. Patients completed a questionnaire and were graded according to the New York Heart Association classification. Doppler echocardiography was performed and blood samples were obtained. 8-hydroxy-2'-deoxyguanosine and lipid peroxidation levels were determined. RESULTS: Significant differences were observed between patients and control subjects in 8-hydroxy-2'-deoxyguanosine and lipid peroxidation levels, at 0.34 (0.54) ng/mL vs 0.04 (0.07) ng/mL (P<.05), and 18 (10) microM vs 8 (3) microM (P<.01), respectively. Subsequent analysis showed that heart failure etiology had a significant effect on the levels of the two markers (P<.05), which were highest in patients with hypertensive cardiomyopathy. CONCLUSIONS: Levels of 8-hydroxy-2'-deoxyguanosine and lipid peroxidation were higher in heart failure patients than in control subjects. The most significant increases were found in patients with hypertensive cardiomyopathy.     

Role of the RIC-3 protein in trafficking of serotonin and nicotinic acetylcholine receptors

Neurotransmitter-gated receptors are assembled in the endoplasmic reticulum and transported to the cell surface through a process that might be of central importance to regulate the efficacy of synaptic transmission (Kneussel and Betz, 2000; Kittler and Moss, 2003). This process is relatively inefficient- what may be the consequence of tight quality controls that guarantee the functional competence of the final product. For this purpose, specific proteins involved in assembly and trafficking of receptors might be required (Keller and Taylor, 1999; Millar, 2003; Wanamaker et al., 2003). The RIC-3 protein could be one of them, as mutations in the ric-3 gene affect maturation of nicotinic acetylcholine receptors (nAChRs) in Caenorhabditis elegans (Halevi et al., 2002). Moreover, the human homolog hRIC-3 showed differential effects when coexpressed with several ligand-gated receptors (Halevi et al., 2003). Thus, it enhanced alpha7 nAChR expression while inhibiting expression of other nAChR subtypes (alpha4beta2 and alpha3beta4) and 5-HT3 serotonin receptors (5-HT3Rs). These opposite effects suggested that the RIC-3 protein might play a key role in the biogenesis of some ligand-gated receptors and prompted us to investigate how it performs its action. Here, we show that the RIC-3 protein acts as a barrier for some receptors like alpha4beta2 nAChRs and 5-HT3Rs, stopping the traffic of mature receptors to the membrane. In contrast, the inefficient transport of alpha7 nAChRs is enhanced by RIC-3 in a process in which certain amino acids at the amphipathic helix located at the C-terminal region of the large cytoplasmic domain are involved.